Our research focuses on studies to delineate the function of nuclear receptor coactivators in the development of mammary gland and breast cancer. Peroxisome proliferator-activated receptor (PPAR) binding protein (PBP, also known as TRAP220/DRIP205/MED1) is one of the coactivators we isolated a few years ago. PBP was implicated in the breast cancer tumorigenesis by our finding that it is overexpressed and amplified in a proportion of breast cancers. The studies supported by this grant over the past five years demonstrated that PBP is essential for the normal mammary gland development. Conditional mammary null mouse model revealed that loss of PBP leads to severely retarded ductal elongation during puberty and lobuloalveolar proliferation during pregnancy and lactation. The impaired mammary stem/progenitor cells, due to PBP gene disruption, were found to be responsible for this phenotype. Studies with mammary cell lines derived from the genetically modified mice demonstrated that PBP is also involved in the growth of cancer stem cells. Furthermore, the development of tamoxifen resistance requires PBP. In addition, a PBP isoform was found to be markedly overexpressed in breast cancer and the overexpression could increase the number of cancer stem cells. Based on these results, we hypothesize that PBP is essential for the growth and differentiation of both normal and cancer mammary stem/progenitor cells. By functioning as a coactivator of several transcription factors including estrogen receptor, PBP serves as a central coordinator to integrate multiple signaling pathways which regulate mammary stem/progenitor cells. The objectives of the proposed studies are to delineate the mechanisms by which PBP regulates the growth and differentiation of mammary stem (normal and cancer) cells. Our specific aims are to: 1). determine the mechanism by which PBP regulates the maintenance, proliferation and differentiation of mammary stem/ progenitor cells; 2). define the role of PBP in the proliferation and differentiation of cancer stem cells; 3). investigate the role of PBP in the development of anti-estrogen resistance. Our proposed studies will generate new information on the biology of mammary stem (normal and cancer) cells, which could provide novel avenues for breast cancer prevention and treatment. [unreadable] [unreadable] [unreadable]